The cardiac responses to stress and cardiomyopathy share a common feature: altered signaling through G protein-coupled receptor (GPCR) pathways that regulate the homeostatic balance of signaling in the heart. This altered signaling can result from changes in the expression or function of receptors, G proteins, as well as down-stream effectors. Restoration of normal homeostasis in cardiomyopathy via GPCR signaling is the basis for medical therapies that target GPCRs, such as the beta-adrenergic receptor (AR). The goal of this proposal is to study the specific roles of beta1 and beta2-ARs in the pathophysiology of cardiomyopathy. Alterations in beta-AR signaling are a central manifestation of chronic sympathetic activation. However, there is controversy as to whether beta-AR downregulation is responsible for the decrease in heart function or is a mechanism to protect the heart from chronic sympathetic stimulation. Recent evidence has linked beta-AR signaling not only to alterations in cardiac function, but to mitogenic pathways which could play a role in cardiac remodeling. We have developed an ideal model to examine the role of beta-ARs in cardiomyopathy: mice with targeted disruptions of beta1 and beta2-ARs. We have preliminary evidence suggesting that absence of the beta1-AR may attenuate the development of cardiomyopathy. Further evidence suggests that absence of the beta2-AR may exacerbate the cardiotoxicity of chronically administered catecholamines. We will utilize our knockout models: 1) To determine the role of beta-ARs in the pathogenesis of cardiomyopathy and whether total absence of beta1 and/or beta2-ARs will attenuate or accelerate cardiac dysfunction in models of cardiomyopathy; 2) To determine whether differences between beta1 and beta2-AR subtypes, both in their role in normal physiology and in their contribution to the cardiomyopathic phenotype, are related to differences in regulated expression or to differences in primary structure. For this purpose, we will utilize a gene exchange model, in which the murine beta1-AR is replaced with a murine beta2-AR under control of the native beta1-AR promoter; 3) To determine the role of beta-AR-mediated interactions between cardiac myocytes and fibroblasts in the pathogenesis of cardiomyopathy; 4) To identify signaling events, mediated by both classical (GS) and alternative (non-GS) pathways, that are altered in cardiomyopathy, and to determine the role of beta-ARs in regulating these pathways.